The purpose of this research is to extend into the treatment of patients with advanced cancer concepts and specific drug regimens that have produced significant increase in therapeutic effectiveness in mice with transplanted tumors. These regimens were developed on the basis of specific biochemical interactions of the several drugs contained therein. The focus will be upon the modulation of the effects of 5-fluroruracil (FUra) by N- phosphonacetyl-L-aspartate (PALA), which depletes intracellular pyrimidine pools, and methylmercaptopurine ribonucleoside (MMPR) or methotrexate, which enhance phosphoryation of FUra by increasing cellular content of phosphoribosyl pyrhosphate (PRPP). Two specific regimens will be studied which produced a significant increase in FUra effect in mice. These are MMPR + PALA + FUra, and PALA + MTX + FUra + leucovorin. Five clinical protocols include both regimens on advanced colon patients, and only the latter regimen in patients with advanced cancers of the breast, head and neck and adenocarcinomas of unknown primary. Concomitant with exploring dose tolerance and therapeutic effect of the two regimens in patient, we will measure the effect that the modulating dose drugs have upon the content of PRPP and UTP in tumors, normal skin, and normal bone arrow. These studies will assess whether or not the proposed biochemical changes occur in patients at the drug doses used and whether or not the changes are selective. Since the administration of uridine enhances therapeutic effect by protecting the host against the toxic effects of therapy, we will plan to add urine (or possibly cytidine) rescue into the regimen when the combined effects in the absence of uridine have been established. By means of these studies we hope not only to improve the therapy of patients with cancer, but also to establish a mechanism for examining the metabolic changes produced by conventional doses of anticancer drugs.
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